It is well known that cancer results from changes in gene expression patterns that are important for cellular regulatory processes such as growth, differentiation, DNA duplication, mismatch repair and apoptosis. It is also becoming more apparent that effective treatment and diagnosis of cancer is dependent upon an understanding of these important processes. Classification of human cancers into distinct groups based on their origin and histopathological appearance has historically been the foundation for diagnosis and treatment. This classification is generally based on cellular architecture, certain unique cellular characteristics and cell-specific antigens only. In contrast, gene expression assays have the potential to identify thousands of unique characteristics for each tumor type (3) (4). Elucidating a genome wide expression pattern for disease states not only could have a enormous impact on the understanding of specific cell biology, but could also provide the necessary link between molecular genetics and clinical medicine (5) (6) (7).
Thyroid carcinoma represents 1% of all malignant diseases, but 90% of all neuroendocrine malignancies. It is estimated that 5-10% of the population will develop a clinically significant thyroid nodule during their life-time (8). The best available test in the evaluation of a patient with a thyroid nodule is fine needle aspiration biopsy (FNA) (9). Of the malignant FNAs, the majority are from papillary thyroid cancers (PTC) or its follicular variant (FVPTC). These can be easily diagnosed if they have the classic cytologic features including abundant cellularity and enlarged nuclei containing intra-nuclear grooves and inclusions (10). Indeed, one third of the time these diagnoses are clear on FNA. Fine needle aspiration biopsy of thyroid nodules has greatly reduced the need for thyroid surgery and has increased the percentage of malignant tumors among excised nodules (11, 12). In addition, the diagnosis of malignant thyroid tumors, combined with effective therapy, has lead to a marked decrease in morbidity due to thyroid cancer. Unfortunately, many thyroid FNAs are not definitively benign or malignant, yielding an “indeterminate” or “suspicious” diagnosis. The prevalence of indeterminate FNAs varies, but typically ranges from 10-25% of FNAs (13-15). In general, thyroid FNAs are indeterminate due to overlapping or undefined morphologic criteria for benign versus malignant lesions, or focal nuclear atypia within otherwise benign specimens. Of note, twice as many patients are referred for surgery for a suspicious lesion (10%) than for a malignant lesion (5%), an occurrence that is not widely appreciated since the majority of FNAs are benign. Therefore when the diagnosis is unclear on FNA these patients are classified as having a suspicious or indeterminate lesion only. It is well known that frozen section analysis often yields no additional information.
The question then arises: “Should the surgeon perform a thyroid lobectomy, which is appropriate for benign lesions or a total thyroidectomy, which is appropriate for malignant lesions when the diagnosis is uncertain both preoperatively and intra-operatively?” Thyroid lobectomy as the initial procedure for every patient with a suspicious FNA could result in the patient with cancer having to undergo a second operation for completion thyroidectomy. Conversely, total thyroidectomy for all patients with suspicious FNA would result in a majority of patients undergoing an unnecessary surgical procedure, requiring lifelong thyroid hormone replacement and exposure to the inherent risks of surgery (16).
Several attempts to formulate a consensus about classification and treatment of thyroid carcinoma based on standard histopathologic analysis have resulted in published guidelines for diagnosis and initial disease management (2). In the past few decades no improvement has been made in the differential diagnosis of thyroid tumors by fine needle aspiration biopsy (FNA), specifically suspicious or indeterminate thyroid lesions, suggesting that a new approach to this should be explored. Thus, there is a compelling need to develop more accurate initial diagnostic tests for evaluating a thyroid nodule.